Burkitt Lymphoma: Revisiting the Pathogenesis of a Virus-Associated Malignancy

Abstract

Burkitt lymphoma (BL), a tumor occurring in endemic, sporadic and AIDS-associated forms, is the classic example of a human malignancy whose pathogenesis involves a specific cellular genetic change, namely, a chromosomal translocation deregulating expression of the c-myc oncogene, complemented in many cases by the action of an oncogenic virus, the Epstein-Barr virus (EBV). Here we review recent work in two complementary areas of research: (1) on cellular genetic changes that occur in addition to the c-myc translocation in BL, in particular the capacity of p53/ ARF pathway breakage or of c-myc mutation to decouple the pro-proliferative effects of c-myc deregulation from its pro-apoptotic effects; and (2) on a postulated role for EBV in BL pathogenesis, through adopting restricted forms of virus latent gene expression that remain compatible with the c-myc-driven growth program but offer the tumor additional protection from apoptosis. We stress the many fundamental questions that remain to be resolved and, in that regard, highlight the general lessons that might be learned through understanding how two other infectious agents, malaria and HIV, dramatically enhance BL incidence.

Epstein-Barr virus LMP2A bypasses p53 inactivation in a MYC model of lymphomagenesis

“…Sporadic BL is found globally with low incidence and has a 15-20% association with EBV. BL is also commonly seen in AIDS patients, with a 30-40% EBV association (2). The increased EBV association seen in patients with HIV or malaria suggests that alterations in immune function may contribute to the link between EBV and BL.…”

Linfoma de Burkitt: características clinicopatológicas, imunoistoquímicas e associação com o vírus de Epstein-Barr (EBV) em populações adulta e pediátrica em diferentes regiões geográficas no Brasil

“…This is clearly distinct from the typical mandibular presentation found in Africa. 2,8,12 Lymph node involvement was more common among the adult than the pediatric population, in concordance with the literature. 26 Therefore, in this extensive analysis of BL from Brazil, the clinical features were similar to the sporadic form of BL seen in the United States and Europe.…”

“…Most EBV+ BL cases (whether endemic, sporadic, or AIDS-associated) typically display more restricted forms of latency, usually latency type I, only expressing EBER1 and EBER2 and EBNA1, 11,12 and, as we and others showed, at least the EBV BART microRNAs. TP53 (also called p53) is a key tumor suppressor gene that is mutated or lost in approximately 50% of all human cancer cases worldwide, including hematologic malignancies.…”

“…44 It has been reported that 30% of endemic BL tumors and up to 70% of long-established BL lines carry mutations in p53. 12 Bhatia et al 45 found p53 mutations in 37% of cases of BL from Argentina and Brazil and concluded that the presence of mutated p53 in BL is independent of the geographic origin of the tumor, the 8;14 chromosomal breakpoint locations, and EBV association. Studies have shown that in some high-grade NHLs, the occurrence of positive immunostaining does not reflect point mutations in the p53 gene and vice versa.…”

“…EBV is present in the majority of endemic cases of BL (up to 100%) and in only 15% to 30% of sporadic cases from the United States. 2,12,28 and North American cases. 35 The South region of Brazil showed the lowest percentage of EBV type B (only 8%), a result similar to sporadic BL in the United States.…”